Cardiac contraction in a healthy human heart is initiated by spontaneous excitation of the sinoatrial (“SA”) node, which is located in the right atrium. The electric impulse generated by the SA node travels to the atrioventricular (“AV”) node where it is transmitted to the bundle of His and to the Purkinje network. The fibers in the Purkinje network branch out in many directions to facilitate coordinated contraction of the left and right ventricles. In some disease states, the heart loses some of its natural capacity to pace properly. Such dysfunction is commonly treated by implanting a pacemaker.
While effectively improving the lives of many patients, implantable pacemakers have certain technical limitations. For example, implantable pacemakers rely on a self-contained power source such as a battery and consequently have a limited lifetime before the power source is in need of replacement. Implantable pacemakers also require pacing leads, which may fail and result in loss of therapy. Hence, an otherwise healthy patient may require multiple surgeries to replace the power source, leads, or the entire implantable pacemaker. Also, implantable pacemakers may not directly respond to physiological signals similar to the way the SA node responds to such signals.
Recently, biological methods of influencing a patient's cardiac cells have been developed, some of which include administering biopharmaceutical compositions that affect cardiac pacing. Developments in genetic engineering have produced methods for genetically modifying cardiac cells to modify non-pacemaking cardiac cells to pacemaker-like cardiac cells or regenerate the pacing capabilities of cells in the conduction system of the heart. For example, Johns and Marban (U.S. Pat. No. 6,214,620) describes a method for modulating the excitability of ventricular cells by controlling the regulation of the expression of certain ion channels (e.g. K+ channels). Marban and Li (PCT Publication No. WO 02/087419) and Sigg et al. (PCT Publication No. WO 05/062890A3) describe methods and systems for modulating electrophysiological behavior of cardiac cells by genetic modification of inwardly rectifying K+ channels (IK1) in quiescent ventricular cells.
Another recent biological approach for modulating cardiac pacing involves implanting into the SA node or other suitable heart regions cells having particular ion channels that are commonly referred to as hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels. For example, see Rosen and Robinson (PCT Publication No. WO 02/098286) and Sigg et al. (PCT Publication No. WO 05/062958A2). Physiologically originating in the SA node, the HCN channels play a prominent role in the control of rhythmic electrical heart activity. Cyclic nucleotides modulate the HCN channel activity, and channel activation occurs upon hyperpolarization rather than depolarization. There are four isoforms of HCN channels (HCN1-4), and each has greater or lesser prevalence in different heart regions. Because the HCN isoforms are directly involved in pacemaker current modulation and activation, implantation of HCN-expressing cells into cardiac tissue that is diseased or experiencing conduction blockage is a viable method for regulating cardiac pacemaker function.